Background: Biologics have gained traction for use in oncology, but have demonstrate clinical variability for efficacy and safety. Therapeutic drug monitoring (TDM) can benefit patients' outcomes from a biologic therapy when the latter has a defined therapeutic window. A clinically relevant therapeutic window may exist for biologics with established exposure-response (E-R) relationships for efficacy and/or safety and a documented maximum tolerated dose (MTD). Additionally, the inter-individual variability (IIV) on the clearance (CL) parameter could determine risks for patients falling outside the proposed therapeutic window...

Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations...

Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2...

INTRODUCTION: Necitumumab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). In the SQUIRE trial, the addition of necitumumab to chemotherapy in squamous cell lung cancer (SCC) significantly improved overall survival (OS) (HR=0.84); in a post-hoc analysis, EGFR copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend towards improved OS (HR=0.70) and progression-free survival (PFS) (HR=0.71) with the addition of necitumumab. We present the analysis of granular EGFR-FISH data from SQUIRE to examine the potential predictive role of high polysomy and gene amplification as both were included in the "FISH-positive" category...

INTRODUCTION: In a retrospective analysis of the SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) study, we investigated the efficacy and safety of single-agent necitumumab continuation therapy in patients with stage IV squamous non-small-cell lung cancer and in a subpopulation of patients with epidermal growth factor receptor (EGFR)-expressing tumors. PATIENTS AND METHODS: Patients were randomized 1:1 for ≤ 6 cycles of gemcitabine and cisplatin either with or without necitumumab...

BACKGROUND: EGFR and its downstream signaling pathway are important targets for cancer therapy. Recently, the monoclonal anti-EGFR antibody Necitumumab in combination with gemcitabine and cisplatin was approved (EMA/14106/2016) for first-line treatment of squamous non-small cell carcinoma (SqNSCLC). Eligibility was restricted to cases with positive EGFR expression. In this context, a ring trial of the Quality Assurance Initiative for Pathology (QuIP(®)) was launched to prepare the German pathology community for a reliable and reproducible, immunohistochemically based biomarker test...

We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard...

BACKGROUND: The combination of necitumumab with gemcitabine-cisplatin significantly improved overall survival (OS) in patients with stage IV squamous non-small-cell lung cancer (NSCLC), in the phase III SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) trial. Paclitaxel-carboplatin was selected as an alternative standard of care in the current phase II study. PATIENTS AND METHODS: Patients were randomized (stratified according to Eastern Cooperative Oncology Group performance status and sex) 2:1 to ≤ six 3-week cycles (Q3W) of paclitaxel and carboplatin with or without necitumumab...

Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method...

The treatment options for metastatic non-small-cell lung cancer (NSCLC) have expanded dramatically in the last 10 years with the discovery of newer drugs and targeted therapy. Epidermal growth factor receptor (EGFR), when aberrantly activated, promotes cell growth and contributes in various ways to the malignant process. EGFR has become an important therapeutic target in a variety of malignancies. Small-molecule tyrosine kinase inhibitors (TKIs) of EGFR are being used to treat advanced NSCLC and are particularly effective in the presence of EGFR mutations...

Non-small cell lung cancer is the most common form of lung cancer, accounting for about 85% of all cases and is further subdivided into adenocarcinoma, squamous cell, and large cell carcinoma. Necitumumab (Portrazza™, Eli Lilly and Company) is an anti-epidermal growth factor receptor monoclonal antibody approved for the first-line treatment of squamous cell non-small cell lung cancer in combination with cisplatin and gemcitabine. The safety and efficacy of necitumumab has been evaluated in two-phase III clinical trials, one demonstrating a lack of efficacy in non-squamous non-small cell lung cancer and another demonstrating improvement in overall survival and progression-free survival in squamous cell non-small cell lung cancer...

Major advances in the treatment of metastatic non-small cell lung cancer have led to significant incremental improvements in patient outcomes. Platinum-based combination therapy remains the cornerstone of first-line therapy. The addition of biologic agents, such as bevacizumab or necitumumab, in selected populations has shown benefit over chemotherapy alone. The advent of maintenance therapy has also improved overall survival outcomes in selected populations of patients. Ongoing studies will further refine optimal treatment in the first-line setting and further advance first-line treatment options...

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